Novel Potent IFN-γ-Inducing CD8+ T Cell Epitopes Conserved among Diverse Bovine Viral Diarrhea Virus Strains

Abstract

Studies of immune responses elicited by bovine viral diarrhea virus (BVDV) vaccines have primarily focused on the characterization of neutralizing B cell and CD4⁺ T cell epitopes. Despite the availability of commercial vaccines for decades, BVDV prevalence in cattle has remained largely unaffected. There is limited knowledge regarding the role of BVDV-specific CD8⁺ T cells in immune protection, and indirect evidence suggests that they play a crucial role during BVDV infection. In this study, the presence of BVDV-specific CD8⁺ T cells that are highly cross-reactive in cattle was demonstrated. Most importantly, novel potent IFN-γ-inducing CD8⁺ T cell epitopes were identified from different regions of BVDV polyprotein. Eight CD8⁺ T cell epitopes were identified from the following structural BVDV Ags: E^rns, E1, and E2 glycoproteins. In addition, from nonstructural BVDV Ags N^pro, NS2-3, NS4A-B, and NS5A-B, 20 CD8⁺ T cell epitopes were identified. The majority of these IFN-γ-inducing CD8⁺ T cell epitopes were found to be highly conserved among more than 200 strains from BVDV-1 and -2 genotypes. These conserved epitopes were also validated as cross-reactive because they induced high recall IFN-γ⁺CD8⁺ T cell responses ex vivo in purified bovine CD8⁺ T cells isolated from BVDV-1- and -2-immunized cattle. Altogether, 28 bovine MHC class I-binding epitopes were identified from key BVDV Ags that can elicit broadly reactive CD8⁺ T cells against diverse BVDV strains. The data presented in this study will lay the groundwork for the development of a contemporary CD8⁺ T cell-based BVDV vaccine capable of addressing BVDV heterogeneity more effectively than current vaccines.